Novel genomic approaches in the elucidation of inherited retinal disease

Inherited retinal dystrophy (IRD) affects the cells at the back of the eyes including the light sensitive cells (photoreceptors) and their companion cells that together enable vision. IRD can be caused by mutations in more than 250 genes that produce the proteins essential for retinal development and function. However in many patients, genetic testing fails to find their mutation, limiting access to effective care and new treatments. This suggests that many genes and mechanisms of disease still need to be identified.

Currently, genetic research has investigated the protein-coding parts of genes, which makes up about 2% of the genome. Whole genome sequencing (WGS) enables complete analysis of the genome including the coding, and non-coding regions within genes, between genes and regulatory regions.

The wide spectrum of normal variations that everybody has makes mutation discovery difficult. In particular, many new disease genes remain to be identified and non-coding mutations are poorly understood. However, these are thought to be an important cause of IRD based on preliminary knowledge from known genes.

Researchers aim to analyse existing WGS data and emerging data from the 100,000 genomes project to:
(1) Unpick the rare non-coding disease mutations from the background of benign variation in known IRD genes and determine their effect on the protein. 
(2) Identify new IRD genes and investigate their function in the retina 
(3) Understand why some gene mutations can cause different or unexpected clinical outcomes. 
(4) Use new technology to investigate certain un-readable regions of the genome that are known to harbour IRD mutations in a subgroup of patients.

WGS data from 636 IRD patients will be analysed using computer-based analysis techniques and tools, online databases and algorithms. The millions of variants will be filtered, ranked and prioritised, with selected mutations further studied using molecular biology techniques to determine their effect on the gene, protein, cell and retina.

New genes and mechanisms of disease will be identified which will improve our understanding of retinal biology, the pathways affected by disease and the implications of different gene dysfunctions. This study will improve researcher’s ability to find disease-causing non-coding mutations, the understanding of disease mechanisms and establish new analysis techniques. New drug targets will be identified since non-coding mutations are particularly promising mutation-blocking therapies. Importantly, patients will obtain a molecular diagnosis, leading to improvements in diagnostic testing and allowing them access to improved clinical care and treatment trials.